HU214337B - Process for the preparation of 1,3,4-thiadiazin-2-one derivatives and pharmaceutical compositions containing them - Google Patents

Abstract

Compounds of formula I (* CHEMICAL STRUCTURE *) I in which R1 and R2 are each independently of one another H or A, R3 is H, OA or O-CmH2m+1-nXn, R4 is -O-CmH2m+1-nXn, X is F or Cl, A is alkyl having 1-6 C atoms, m is 1, 2, 3, 4, 5 or 6 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13, and their salts have positive ionitropic activity and vasodilating action, and promote circulation. In addition, the compounds can be employed for the treatment of asthmatic disease and memory disorders, and have anti-depressive and anti-inflammatory properties.

Description

The present invention relates to the preparation of 1,3,4-thiadiazin-2-one derivatives of formula (I) and pharmaceutical compositions containing them. In the general formula (I)

R ¹ and R ² independently of one another are hydrogen or A;

R ^{3 is} hydrogen, -OA- or -OC _m H 2 _{m +} ]. _n X _n ,

R ⁴ -OC _m H2 _m + i-nX _n

X is a fluorine or chlorine atom,

C 1 -C 6 alkyl means m is 1, 2, 3, 4, 5 or 6 and n is 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12 or 13. The compounds of the formula I are phosphodiesterase

Due to their inhibitory effect, enzyme IV is useful in the treatment of heart failure.

Scope of the description: 6 pages (including 1 page figure)

HU 214 337 B

HU 214 337 Β

The present invention relates to novel 1,3,4-thiadiazin-2-one derivatives of the formula (I) and their salts and to pharmaceutical compositions containing them. In the general formula (I)

R ¹ and R ² are each independently hydrogen or

The group

R ^{3 is} hydrogen, -OA-, or -OC _m H _{2 m +} i - _n X _n ,

R ⁴ OC _m H _2m + i. _n X _n ,

X is a fluorine or chlorine atom,

C 1 -C 6 alkyl means m is 1, 2, 3, 4, 5 or 6 and n is 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12 or 13.

Thiadiazinone derivatives are known, inter alia, from German Patent Application DE 3 7 19 031.

It was an object of the present invention to provide novel compounds having valuable properties, in particular those useful in the preparation of medicaments.

The compounds of formula I have been found to possess valuable pharmacological properties with good tolerability. In particular, these compounds act on cardiac muscle strength (positive inotropic effect); in addition, they have a vasodilating effect and thereby promote blood flow. The vasodilator and cardiac effects can be detected, for example, in anesthetized or awake dogs, cats, monkeys, or dwarf pigs, in isolated cardiac preparations of rat, guinea pig, cat or dog (e.g. are known [Arzneimittelforschung, Vol. 31 (I) la. No. 1981, pp. 141-170. or Schliep et al., 9th International Congress of Pharmacology, London, Abstracts 9P].

The compounds are also useful in the treatment of asthma. The anti-asthma effect can be demonstrated, for example, by the method of T. Olsson (Acta Allergologica 26, 438-447 (1971)).

The compounds also have a cerebroprotective effect and can be used to treat memory loss; they also have anti-depressant and antipyretic properties.

As described above, these compounds are useful in human and veterinary medicine. They can also be used as intermediates for the preparation of further pharmaceutical agents.

The present invention relates to a process for the preparation of a compound of formula (I) wherein a compound of formula (II) wherein r ', r ² , r ³ and R ⁴ are as defined above.

Z is bromo, chloro or iodo, or a reactive esterified hydroxy group with a compound of formula III wherein

^R5 represents a sodium or potassium atom or an ammonium group or a A-, and

A is as defined above, which is reacted and, if desired, converted to a salt of the base of formula I obtained by treatment with an acid.

Above and below, R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,

The groups A, X and Z and the parameters m and n have the same meaning as given in formulas (I), (II) and (III), unless otherwise specified.

In the formulas, the alkyl group is preferably straight chain, preferably having 1,2,3 or 4 carbon atoms and preferably methyl, more preferably ethyl or propyl, more preferably isopropyl, butyl, isobutyl, secondary butyl, tert-butyl or n-pentyl or isopentyl.

The alkoxy group is preferably a straight chain, preferably having 1, 2 or 3 carbon atoms and preferably a methoxy group, more preferably ethoxy or propoxy, and more preferably isopropoxy, butoxy, isobutoxy, secondary butoxy, tert-butoxy, pentoxy or isopentoxy.

R ^1, R ^2, R ³ and R ⁴ groups are particularly preferred as follows: ^R1 is hydrogen; R ^{2 is} methyl or ethyl; R ^{3 is} methoxy and R ^{4 is} difluoromethoxy. When R ³ and / or R ⁴ are other than hydrogen, they are preferably in the 3- or 4-position of the phenyl ring. Preferably X is fluorine. Preferably m and n are 1, 2 or 3, however n is preferably 4, 5, 6 or 7.

In particular, the present invention relates to compounds of formula (I) wherein at least one of said groups has the following preferred meaning. Certain preferred groups of these compounds may be expressed by the following formulas la-d, which correspond to formula (I) and in which non-designated groups have the same meaning as in formula (I), but wherein R ^{3 is} a phenyl ring 4 R ^{4 is in} the 3 position of the phenyl ring,

R ^{1 is} hydrogen,

R ^{2 is} hydrogen or alkyl,

R ^{3 is} difluoromethoxy,

R ^{4 is} alkoxy;

in formula 1b, R ^{3 is in} the 4-position of the phenyl ring, R ^{4 is in} the 3-position of the phenyl ring,

R ^{1 is} hydrogen,

R ^{2 is} methyl or ethyl,

R ^{3 is} difluoromethoxy,

R ^{4 is} alkoxy;

In formula Ic, R ^{3 is in} the 4-position of the phenyl ring, R ^{4 is in} the 3-position of the phenyl ring,

R ^{1 is} hydrogen,

R ^{2 is} methyl or ethyl,

R ^{3 is} difluoromethoxy, trifluoromethoxy, -OC ₂ H ₅ . _{n and n} M, is wherein n is 1,2, 3,4 or 5 and

R ^{4 is} alkoxy;

In the formula R ^3, R ^{3 is in} the 4-position of the phenyl ring, R ^{4 is in} the 3-position of the phenyl ring,

R ¹ is hydrogen,

R ² is hydrogen, methyl or ethyl,

R ^{3 is} difluoromethoxy, trifluoromethoxy, -OC 7 H 5. _n F _n ,

-O ₃ 7- _n F _n , -OC ₄ H ₉ . F _n is _n, wherein n is 1,2, 3,4 or 5, OC ₃ H _{7th n} F _n _and OC ₄ H ₉ . in case _n F _n groups with 6 or 7 and OC ₄ H ₉ _ _n M _n for group likewise 8 or 9 and

R ^{4 is} methoxy or ethoxy.

Otherwise, the compounds of formula (I) may be prepared by methods known per se, such as those described in the literature (e.g., Houben-Weyl, Methoden der Organischen Chemie, Georg Thieme-Verlag, Stuttgart) under reaction conditions are known and used. Alternatively, other per se known variations of the process may be used instead.

In the compounds of formula II, R ¹ , R ² , R ³ and R ⁴ are as defined above, while Z is preferably chlorine or bromine. When X is a reactive esterified hydroxy group, it is preferably a C 16 alkylsulfonyloxy group such as C 6 -C 10 methanesulfonyloxy or arylsulfonyloxy group such as benzene, p-toluene or 1- or 2-naphthalenesulfonyloxy.

In the compounds of formula (III), R ⁵ is preferably methyl or ethyl, but may also be sodium or potassium or ammonium.

If desired, the starting materials may also be formed in situ by reacting them directly into the compounds of formula (I) rather than isolating them from the reaction mixture. On the other hand, it is also possible to conduct the reaction stepwise, whereby additional intermediates can be isolated.

The starting materials of the formulas II and III are partially known. Where new can be prepared by methods known per se. For example, the ketones of formula II can be obtained from the corresponding phenyl derivatives by Friedel-Crafts synthesis with Y-CO-CR'R ² -Z wherein Y is chlorine or bromine.

In particular, the ketones of formula (II) are reacted with the compounds of formula (III) in the presence or absence of inert solvents at temperatures between -20 ° C and about +150 ° C, preferably between 20 ° C and 100 ° C. Suitable solvents are, for example, hydrocarbons such as benzene, toluene, xylene or mesitylene; halogenated hydrocarbons such as dichloromethane, trichloroethylene or chlorobenzene; alcohols such as methanol, ethanol or isopropanol; glycols and glycol ethers such as ethylene glycol, diethylene glycol, 2-methoxyethanol; nitriles such as acetonitrile; ethers such as tetrahydrofuran or dioxane; amides such as dimethylformamide (DMF); sulfoxides such as dimethyl sulfoxide. Mixtures of these solvents may also be used.

Alternatively, a compound of formula (I) which, however, contains one or two patents instead of R ³ and / or R ⁴ , may contain a compound of formula R ³ -Z or R ⁴ -Z in which R ³ , R ⁴ and Z is as defined above, to react. The etherification of the hydroxyl groups is carried out by methods well known in the art, such as those described in basic chemical science collections (e.g., Houben-Weyl, Methoden Der Organischen Chemie, Georg Thieme Verlag, Stuttgart; or Organic Reactions, John Wiley and Sons Inc., New York). which are known and used for such reactions. In addition, other live variants known per se, not specifically mentioned herein, may be used.

The compounds of formula I may have one or more centers of asymmetry. In this case they are usually formed as racemates. The resulting racemates can be mechanically or chemically separated into optical antipodes in a manner known per se. Preferably, diastereomers are formed from the racemate mixture by reaction with an optically active resolving agent. It is, of course, also possible to prepare the compound of formula (I) by the methods described above using optically active starting materials.

The invention further relates to a process for the use of the compounds of the formula I and / or their physiologically acceptable salts for the preparation of a pharmaceutical composition. Meanwhile, the compounds are formulated in a suitable formulation together with at least one solid, liquid and / or semi-liquid carrier and / or other excipient and optionally one or more further active ingredients.

These preparations can be used as medicaments in human and veterinary medicine. Suitable carriers are organic and inorganic compounds which are suitable for enteral (e.g. oral), parenteral or topical administration and do not react with the novel compounds; suitable carriers include water, vegetable oils, benzyl alcohol, polyethylene glycol, glycerol triacetate, gelatin, carbohydrates such as lactose, starch, magnesium stearate, talc, petrolatum. In particular, tablets, dragees, capsules, syrups, juices or drops, rectal suppositories, solutions for parenteral use, preferably oily or aqueous solutions, suspensions, emulsions or implants, ointments, creams or powders for topical administration are particularly suitable. The novel compounds can also be freeze-dried and the resulting lyophysates used, for example, for the preparation of injectables. The compositions herein may be sterilized and / or used with excipients such as lubricants, preservatives and / or crosslinking agents, emulsifiers, salts, buffering agents, colorants, flavors and / or flavoring agents to influence the osmotic pressure. If desired, they may contain additional active ingredients such as one or more vitamins.

The compounds of formula I are useful in the treatment of diseases, in particular heart failure, and in the therapeutic treatment of human and animal organisms.

In addition, the compounds of the invention are usually administered in a manner similar to known positive inotropic agents (e.g., AMRINON), preferably

The dosage range is about 1 to 100 mg, especially 2 to 20 mg. The daily dose is preferably from 0.02 to 2 mg per kilogram of body weight. However, the specific dosage for each patient will depend on various factors such as the efficacy of the compound used, age, weight, general health, sex, nutrition, time and route of administration, rate of excretion, drug combination and disease treated. severity. Oral administration is preferred. Compared to the digitalis glycosides used to date in the treatment of heart failure, the compounds of formula I exhibit a broader spectrum of therapeutic effects and better peripheral relief.

The compounds were tested for their phosphodiesterase IV (PDE IV) inhibitory activity on guinea-pig heart by the method of T. Olsson (Acta Allergologica 26, 438-447 (1971)), comparing 5- (3,4-dimethoxyphenyl) known in the art. -6-methyl-3,6-dihydro-1,3,4-thiadiazon-2-one (c) in the table below) which is structurally related to the compounds of the invention. Among the compounds of the invention, 5- [3-methoxy-4- (difluoromethoxy) phenyl] -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one according to Example 1 [ (a)] and (+) - 5- [3-methoxy-4- (difluoromethoxy) phenyl] -6-ethyl-3,6-dihydro-1,3,4-thiadiazine in Example 7 -2-on [Table b)]. The results are shown in the table below.

Table: PDE IV inhibition, IC ₅ Q values [mol / 1]

Compound and Example Comment IC50 (Mol / 1) a) (1) racemate ⁸ 4xl0- b) (7) a) (+) -enan- enantiomer 3 + 10 ⁸ c) known (racemate) 2 + 10 ⁷

The table shows that the compounds of the present invention have significantly better activity than the known structurally related active ingredient.

In the following production examples, "usual processing" means:

If necessary water or dilute sodium hydroxide solution is added, the mixture is extracted with an organic solvent such as ethyl acetate, chloroform or dichloromethane, the organic phase is separated off, dried over sodium sulfate, filtered, evaporated and the product is chromatographed and / or crystallized.

Above and below all temperatures are given in ° C.

Example 1

7.0 g 1- [3-methoxy-4- (difluoromethoxy) phenyl] -2-bromobutan-1-one [1- (4-hydroxy-3-methoxyphenyl) butane-1- from tin by etherification with chlorodifluoromethane followed by bromination. Dissolve in 50 ml of acetonitrile and add 2.6 g of hydrazinothio-acetic acid methyl ester and reflux for 2 hours. The solvent was removed in vacuo and the reaction was worked up in the usual manner.

5- [3-Methoxy-4- (difluoromethoxy) -phenyl] -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one is obtained. 97 ° C.

Example 2

Similarly to Example 1, the methyl hydrazinothioic acid was reacted with 1- [4- (difluoromethoxy) -3-methoxyphenyl] -2-bromoethane-1-tin: 5- [3-methoxy-4- (di-fluoromethoxyphenyl) -3,6-dihydro-1,3,4-thiadiazin-2-one, m.p. 120 ° C.

Example 3 (not covered)

5.4 g 5- (3-Methoxy-4-hydroxyphenyl) -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one [1- (4-hydroxy-3-methoxyphenyl) ) -2-Bromobutan-1-one is reacted with methyl hydrazinothioic acid to give a solution of 3-iodo-1,1,2,2,3-pentafluoropropane in tetrahydrofuran and the reaction mixture is stirred for 2 hours. bring to a boil. The solvent was then removed in vacuo and the residue worked up in the usual manner. 5- [3-Methoxy-4- (1,2,3,2,3-pentafluoropropoxy) phenyl] -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one is obtained. .

Example 4

As in Example 1, the methyl hydrazinothioacetic acid is reacted with 1- [bis-3,4-difluoromethoxy-phenyl-2-bromoethane-1-tin to give 5- [bis-3,4- (difluoromethoxy) ) -phenyl] -3,6-dihydro-1,3,4-thiadiazin-2-one.

Example 5

As in Example 1, the methyl hydrazinothio-formic acid is reacted with 1- [4- (2,2,2-trifluoroethoxy) phenyl] -2-bromobutane-1-tin to give 5- [4- (2, 2,2-Trifluoroethoxy) phenyl] -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, m.p. 102 ° C.

The following compounds were prepared analogously to 1- [3-methoxy-4- (2,2,2-trifluoroethoxy) phenyl] -2-bromobutane-1-tin:

5- [3-methoxy-4- (2,2,2-trifluoroethoxy) phenyl] -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, m.p. 123-125 ° C;

With 1- [3-methoxy-4- (2,2,2-trifluoroethoxy) phenyl-2-bromoethane-1-tin:

5- [3-methoxy-4- (2,2,2-trifluoroethoxy) phenyl] -3,6-dihydro-1,3,4-thiadiazin-2-one, m.p. 120 ° C;

l- [3- (2,2,2-trifluoro-ethoxy) -4-methoxyphenyl] -2-bromo-butane-1-tin:

5- [3- (2,2,2-Trifluoroethoxy) -4-methoxyphenyl] -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, m.p. 120-121 ° C;

l- (3-difluoromethoxy-4-methoxyphenyl) -2-bromo-butane-1-tin:

5- (3-Difluoromethoxy-4-methoxyphenyl) -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, m.p. 105 ° C.

Example 6

Chromatographic enantiomer separation using a chiral stationary phase (CHIRASPHER ^r ) racemic 5- (3-methoxy-4-difluoromethoxyphenyl) -6-ethyl-3,6-dihydro-1,3,4-thiadiazine-2 from op. 97 ° C; Example 1) starting from (+) - 5- (3-methoxy-4-difluoromethoxyphenyl) -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one

And (-) - 5- (3-methoxy-4-difluoromethoxyphenyl) -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one.

Analogously from racemic 5- [3- (2,2,2-trifluoroethoxy) -4-methoxyphenyl] -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one (m.p. 120-121 ° C (obtained according to Example 5) starting from:

(+) - 5- [3- (2,2,2-Trifluoroethoxy) -4-methoxyphenyl] -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one; (-) - 5- [3- (2,2,2-Trifluoroethoxy) -4-methoxyphenyl] -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one is obtained. .

The following examples relate to pharmaceutical compositions containing a compound of formula (I) or an acid addition salt thereof.

Example A: tablets kg of 5- [3-methoxy-4- (difluoromethoxy) phenyl] -6-ethyl-3,6-dihydro-1,3,4-thiadiazin-2-one, 10 kg lactose, A mixture of 6 kg of microcrystalline cellulose, 6 kg of potato starch, 1 kg of polyvinylpyrrolidone, 0.8 kg of talc and 0.1 kg of magnesium stearate is conventionally compressed into tablets so that each tablet contains 10 mg of the active ingredient.

Example B: Dragees

In Example A, tablets are compressed and then conventionally coated with sucrose, potato starch, talc, carrier and coloring.

Example C: Capsules kg of 5- (3-methoxy-4-difluoromethoxyphenyl) -3,6-dihydro-1,3,4-thiadiazin-2-one is conventionally filled into hard gelatin capsules so that each capsules containing 5 mg of the active ingredient.

Example D: A solution of ampoules in kg of 5- (3-methoxy-4-difluoromethoxyphenyl) -3,6-dihydro-1,3,4-thiadiazin-2-one in 30 liters of 1,2-propanediol was sterile filtered vials, lyophilized under sterile conditions and sealed. Per ampoule! amount of active ingredient is 2 mg.

Similarly, tablets, dragees, capsules and ampoules of any one or more of the active compounds of formula (I) and / or their physiologically acceptable acid addition salts are prepared.

Claims (2)

A process for the preparation of 1,3,4-thiadiazin-2-one derivatives of the formula I and their salts - in which R ¹ and R ² are independently hydrogen or The group R ^{3 is} hydrogen, -OA-, or -OC _m H _{2m +} 1. _n X _n , R ⁴ -O-C _m H _{2nl + 1} _ _n X _n , X is a fluorine or chlorine atom, C 1 -C 6 alkyl means m is 1, 2, 3, 4, 5 or 6 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or 13-. , characterized in that a compound of the formula II in which R ¹ , R ² , R ³ and R ⁴ are as defined above, Z is bromo, chloro or iodo, or a reactive esterified hydroxy group with a compound of formula III wherein R ⁵ is sodium or potassium, or A or ammonium; and A is as hereinbefore defined and, if desired, the resulting base of formula (I) is converted into one of its salts by treatment with an acid. A process for the preparation of a pharmaceutical composition comprising the compound of formula (I) and / or the physiologically acceptable salt thereof according to claim 1 together with at least one solid, liquid or semi-liquid carrier and / or other excipient. we. HU 214 337 Β Int. C1ÁC 07 D 285/16 H ₂ N-NH-CS-OR ⁵